title: Time-dependent expression of endothelin-1 in lungs and the effects of TNF-α blocking peptide on acute lung injury in an endotoxemic rat model.
abstract: Endothelin (ET)-1 is a potent vasoconstrictor that has been implicated in the pathogenesis of a number of diseases, and some studies suggest that circulating ET-1 is elevated in sepsis. The present study investigated whether ET plays a role in sepsis-mediated acute lung injury and whether its expression could be down regulated by blockade of TNF-α in septic lung. Male Wistar rats at 8 weeks of age were administered with either saline or lipopolysaccharide (LPS) at different time points (1, 3, 6 and 10 h) and various tests were then performed. The features of acute lung injury were observed at 1 h after LPS administration, which gradually became severe with time. Systolic and diastolic pressures were reduced just about one hour after LPS administration, whereas pulmonary TNF-α levels were significantly increased at various time points after LPS administration. LPS induced a time-dependent expression of ET-1 and ET(A) receptor in the lungs compared to control, peaking and increasing by 3 fold at 6 h after induction of endotoxemia, whereas levels of ET(B) receptor, which has vasodilating effects, were remarkably down regulated time-dependently. We conclude that time-dependent increase of ET-1 and ET(A) receptor with the down regulation of ET(B) receptor may play a role in the pathogenesis of acute lung injury in endotoxemia. Finally, treatment of LPS-administered rats with TNF-α blocking peptide for three hours significantly suppressed levels of pulmonary ET-1. These data taken together, led us to conclude that differential alteration in ET expression and its receptors may be mediated by TNF-α and may, in part, account for the pathogenesis of acute lung injury in endotoxemia.
authors.affiliation: Division of Gene Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. jsubrine@gmail.com
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Sohel
authors.initials: S
authors.lastname: Zaedi
authors.forename: Sayeeda
authors.initials: S
authors.lastname: Nusrat Sultana
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Iwashima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sawamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Gando
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism*; D019446:Endotoxemia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D019344:Lactic Acid / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D008070:Lipopolysaccharides; D010455:Peptides; D017466:Receptors, Endothelin; D014409:Tumor Necrosis Factor-alpha; D019344:Lactic Acid